Congenital heart defects (CHD) occur at a rate of 1 per 100 live births and have significant mortality and morbidity rates. While great progress has been in understanding heart development, the genetic contribution of CHD remains largely unknown. Nearly half of individuals with trisomy 21, the cause of Down Syndrome (DS), have much higher rates of CHD. Complete atrioventricular septal defects (AVSD) occur at a rate of nearly 1 in 5 DS patients, which corresponds to a 2000-fold increased occurrence relative to the general population. This project aims to test the hypothesis that copy number variation (CNV) causes the dramatically higher rates of AVSD among individuals with DS. We will first perform array comparative genomic hybridization (aCGH) using a high density (385K probes) microarray covering chr21 at a mean density of 1 probe per 70 base pairs with a trisomy 21 reference in order to test the role of chr21 CNVs on AVSD. Whole genome detection of CNVs will be carried out with Affymetrix Genome-Wide Human SNP Array 6.0 microarray in the 400 cases, 400 controls, and 800 parents of cases. A subset of the CNVs detected will be validated with Taqman genotyping. Statistical analyses of common and rare CNVs will be undertaken to test the hypotheses that common/rare CNVs contribute to AVSD susceptibility in DS individuals. Finally, the genome-wide SNP data will be used to identify common AVSD susceptibility variants in both whole genome association and transmission disequilibrium test (TDT) frameworks. These studies will allow an exhaustive evaluation of the role of genome-wide CNVs and common SNPs on AVSD susceptibility and complements ongoing funded patient collection. PUBLIC HEALTH RELEVANCE: The genetic causes of congenital heart defects (CHD) remain largely undiscovered. Individuals with trisomy 21, the cause of Down Syndrome, have much higher rates of CHD, including the very severe atrioventricular septal defects (AVSD). Our project aims to identify both structural genetic variation and common single nucleotide polymorphisms that act to increase the risk of AVSD. Identifying the genetic basis of this disorder can provide insights into the origins of CHD and ultimately lead to improved methods of treatment and prevention.